Abstract

Background

Perinatal asphyxia (PA) is a major cause of brain damage and neurodevelopmental impairment
in infants. Recent investigations have shown that experimental sublethal fetal asphyxia
(FA preconditioning) protects against a subsequent more severe asphyctic insult at
birth. The molecular mechanisms of this protection have, however, not been elucidated.
Evidence implicates that inflammatory cytokines play a protective role in the induction
of ischemic tolerance in the adult brain. Accordingly, we hypothesize that FA preconditioning
leads to changes in the fetal cytokine response, thereby protecting the newborn against
a subsequent asphyctic insult.

Methods

In rats, FA preconditioning was induced at embryonic day 17 by clamping the uterine
vasculature for 30 min. At term birth, global PA was induced by placing the uterine
horns, containing the pups, in a saline bath for 19 min. We assessed, at different
time points after FA and PA, mRNA and protein expression of several cytokines and
related receptor mRNA levels in total hemispheres of fetal and neonatal brains. Additionally,
we measured pSTAT3/STAT3 levels to investigate cellular responses to these cytokines.

Results

Prenatally, FA induced acute downregulation in IL-1β, TNF-α and IL-10 mRNA levels.
At 96 h post FA, IL-6 mRNA and IL-10 protein expression were increased in FA brains
compared with controls. Two hours after birth, all proinflammatory cytokines and pSTAT3/STAT3
levels decreased in pups that experienced FA and/or PA. Interestingly, IL-10 and IL-6
mRNA levels increased after PA. When pups were FA preconditioned, however, IL-10 and
IL-6 mRNA levels were comparable to those in controls.

Conclusions

FA leads to prenatal changes in the neuroinflammatory response. This modulation of
the cytokine response probably results in the protective inflammatory phenotype seen
when combining FA and PA and may have significant implications for preventing post-asphyctic
perinatal encephalopathy.